Pregnancy outcomes in infertile patients with endometrial hyperplasia with or without atypia undergoing in vitro fertilization: the early-follicular long protocol is superior to midluteal long protocol.

Background: Although in vitro fertilization (IVF) in infertile patients with endometrial hyperplasia is common after drug treatment, the pregnancy outcomes are often unsatisfactory. Till date, no studies have reported the outcome of patients with endometrial hyperplasia treated using early-follicular long (EL) protocol and midluteal long (ML) protocol. Objective: To evaluate the pregnancy outcomes and disease prognosis of patients with endometrial hyperplasia with or without atypia undergoing IVF treatment with EL protocol or ML protocol. Methods: This was a retrospective study in university-affiliated reproductive medical center. A total of 138 patients with endometrial hyperplasia undergoing IVF treatment were included to compare the pregnancy outcomes and disease prognosis between EL and ML protocols. We further matched 276 patients with normal endometrium to compare the pregnancy outcomes between patients with endometrial hyperplasia and patients with normal endometrium under different controlled ovarian stimulation (COS) protocol. Results: In patients with endometrial hyperplasia, the clinical pregnancy rate (CPR) and live birth rate (LBR) were significantly higher in EL protocol than in ML protocol (61.8% vs. 43.5%, P=0.032; 50.0% vs. 30.6%, P= 0.022). In the ML protocol, patients with endometrial hyperplasia had significantly lower CPR and LBR than those with normal endometrium (43.5% vs. 59.7%, P=0.037; 30.6% vs. 49.2%, P=0.016). While in the EL protocol, they achieved similar CPR and LBR as patients with normal endometrium (61.8% vs. 69.7%, P=0.232; 50.0% vs. 59.9%, P=0.156). In patients with endometrial hyperplasia, COS protocol was an independent factor affecting clinical pregnancy (adjusted odds ratio [OR] 2.479; 95% confidence interval [CI] 1.154-5.327) and live birth (adjusted OR 2.730; 95% CI 1.249-5.966). After 1-10 years of follow-up, no significant difference was found in the recurrence rate of endometrial lesions between both treatment groups. Conclusions: For patients with endometrial hyperplasia undergoing IVF treatment, the EL protocol is superior to ML protocol, and in the EL protocol, they can achieve similar pregnancy outcomes as patients with normal endometrium.

Diagnosis and management of endometrial hyperplasia: A UK national audit of adherence to national guidance 2012-2020.

BACKGROUND: Endometrial hyperplasia (EH) is a precusor lesion for endometrial cancer (EC), the commonest gynaecological malignancy in high-income countries. EH is a proliferation of glandular tissue, classified as either non-atypical endometrial hyperplasia (NEH) or, if the cytological features are abnormal, atypical endometrial hyperplasia (AEH). The clinical significance of AEH is that patients face both a high risk of having occult EC and a high risk of progression to EC if untreated. Recommendations on the care of women with EH were introduced by United Kingdom-wide guidance (Green-top Guide No. 67, 2016). National adherence to guidance is unknown. We aimed to describe the care of patients with EH; to compare the patterns of care for those with EH with national guidance to identify opportunities for quality improvement; and to compare patterns of care prior to and following the introduction of national guidance to understand its impact. METHODS AND FINDINGS: In this UK-wide patient-level clinical audit, we included 3,307 women who received a new histological diagnosis of EH through a gynaecology service between 1 January 2012 and 30 June 2020. We described first-line management, management at 2 years, and surgical characteristics prior to and following national guidance for EH using proportions and 95% confidence intervals (CIs) and compared process measures between time periods using multilevel Poisson regression. Of the 3,307 patients, 1,570 had NEH and 1,511 had AEH between 2012 and 2019. An additional 85 patients had NEH and 141 had AEH during 2020. Prior to national guidance, 9% (95% CI [6%, 15%]) received no initial treatment for NEH compared with 3% (95% CI [1%, 5%]) post-guidance; 31% (95% CI [26%, 36%]) and 48% (95% CI [43% 53%]) received an intrauterine progestogen, respectively, in the same periods. The predominant management of women with AEH did not differ, with 68% (95% CI [61%, 74%]) and 67% (95 CI [63%, 71%]) receiving first-line hysterectomy, respectively. By 2 years, follow-up to histological regression without hysterectomy increased from 38% (95% CI [33%, 43%]) to 52% (95% CI [47%, 58%]) for those with NEH (rate ratio (RR) 1.38, 95% CI [1.18, 1.63] p < 0.001). We observed an increase in the use of total laparoscopic hysterectomy among those with AEH (RR 1.26, 95% CI [1.04, 1.52]). In the later period, 37% (95% CI [29%, 44%]) of women initially diagnosed with AEH who underwent a first-line hysterectomy, received an upgraded diagnosis of EC. Study limitations included retrospective data collection from routine clinical documentation and the inability to comprehensively understand the shared decision-making process where care differed from guidance. CONCLUSIONS: The care of patients with EH has changed in accordance with national guidance. More women received first-line medical management of NEH and were followed up to histological regression. The follow-up of those with AEH who do not undergo hysterectomy must be improved, given their very high risk of coexistent cancer and high risk of developing cancer.

PTEN mutation predicts unfavorable fertility preserving treatment outcome in the young patients with endometrioid endometrial cancer and atypical hyperplasia.

OBJECTIVE: This study aimed to investigate the impact of molecular classification and PTEN, KRAS and PIK3CA gene mutation on the outcome of fertility-preserving treatment in the patients with endometrioid endometrial cancer (EEC) and endometrial atypical hyperplasia (EAH). METHODS: This is a single-center retrospective study. A total of 135 patients with EEC and EAH receiving fertility-preserving treatment and molecular classification were reviewed. The distribution of the four types of molecular classification was described. The impact of non-specific molecular profile (NSMP), mismatch repair-deficiency (MMRd), and PTEN, KRAS and PIK3CA gene mutation on the outcome of fertility-preserving treatment was analyzed. RESULTS: Of the patients analyzed, 86.7% (117/136) were classified as having NSMP; 14 (10.4%), MMRd; 1 (0.7%), POLEmut EAH; and 3 (2.2%), p53abn EEC. The patients having NSMP and MMRd achieved similar 16-, 32-, and 48-week complete response rates. The patients harboring tier I and tier II PTEN mutations (PTENmut-Clin) achieved lower cumulative 32-week CR rates than those with PTEN-others (without PTENmut-Clin) (22/47, 46.8% vs. 50/74, 67.6%; p=0.023; odds ratio=0.422; 95% confidence interval [CI]=0.199-0.896). Insulin-resistance (hazard ratio [HR]=0.435; 95% CI=0.269-0.702; p=0.001) and PTENmut-Clin (HR=0.535; 95% CI=0.324-0.885; p=0.015) were independent negative predictors for lower 32-week CR rates. CONCLUSION: PTENmut-Clin is an independent risk factor for unfavorable fertility-preserving treatment outcomes in the patients with EEC and EAH. The patients with MMRd receiving fertility-preserving treatment achieved outcomes similar to those of the patients with NSMP. The molecular profiles might guide fertility-preserving treatment in the prognosis and clinical decisions.

Impacts of ovarian reserve on conservative treatment for endometrial cancer and atypical hyperplasia.

Objectives: Real-world data indicated that some endometrial atypical hyperplasia (EAH) and early endometrial carcinoma (EEC) patients of fertility preservation had a normal ovarian reserve, while some had a decreased ovarian reserve (DOR). This study was designed to investigate the effect of baseline ovarian reserve on the treatment of EAH and EEC patients who ask for preservation of fertility. Methods: This was a prospective cohort study conducted at a single university-affiliated fertility center. A total of 102 EAH and EEC patients who received fertility-preserving treatment between March 2019 and August 2020 were included and divided into a DOR group (n=22) and a non-DOR group (n=80). Results: The 32-week CR rate of the non-DOR group was significantly higher than that of the DOR group (60.3% vs. 33.3%, P =0.028). The DOR group had a longer treatment duration to achieve CR than the non-DOR group (40.07 vs. 29.71 weeks, P=0.008, HR: 0.54, 95% CI: 0.36-0.86). Multivariate logistic regression analyses demonstrated that DOR (OR: 0.35, 95% CI: 0.13-0.99, P=0.049) and BMI ≥25 kg/m2 (OR: 0.40, 95% CI: 0.17-0.92, P=0.031) were negatively associated with 32-week CR. Conclusions: Decreased baseline ovarian reserve is negatively correlated with the efficacy of fertility-preserving treatment in EAH and EEC patients, as this group has a lower CR rate and a longer treatment duration to achieve CR than those without DOR.

Endometrial Hyperplasia.

The objectives of this Clinical Expert Series on endometrial hyperplasia are to review the etiology and risk factors, histologic classification and subtypes, malignant progression risks, prevention options, and to outline both surgical and nonsurgical treatment options. Abnormal uterine and postmenopausal bleeding remain the hallmark of endometrial pathology, and up to 10-20% of postmenopausal bleeding will be either hyperplasia or cancer; thus, immediate evaluation of any abnormal bleeding with either tissue procurement for pathology or imaging should be undertaken. Although anyone with a uterus may develop atypical hyperplasia, also known as endometrial intraepithelial neoplasia (EIN), genetic predispositions (eg, Lynch syndrome), obesity, chronic anovulation, and polycystic ovarian syndrome all markedly increase these risks, whereas use of oral contraceptive pills or progesterone-containing intrauterine devices will decrease the risk. An EIN diagnosis carries a high risk of concomitant endometrial cancer or eventual progression to cancer in the absence of treatment. The definitive and curative treatment for EIN remains hysterectomy; however, the obesity epidemic, the potential desire for fertility-sparing treatments, the recognition of varying rates of malignant transformation, medical comorbidities, and an aging population all may factor into decisions to employ nonsurgical treatment modalities.

[Analyze of obesity indicators and effect of fertility preservation treatment in patients with endometrial atypical hyperplasia and early endometrial cancer].

Objective: To investigate the clinical features of obesity indicators in patients with endometrial atypical hyperplasia (EAH) and early endometrial cancer (EC) and analyze the relationship between these indexes and effect of fertility preservation therapy. Methods: The clinical data of patients with EAH, EC and endometrial benign lesions treated in Peking University People's Hospital from January 1, 2018 to June 30, 2021 who required fertility-sparing treatment were collected, and obesity indicators were calculated and analyzed retrospectively. Results: (1) Obesity indicators: the obesity [body mass index (BMI) ≥28 kg/m2] rate of patients with fertility preservation treatment was 40% (32/80), and abdominal obesity [waist circumference (WC) ≥80 cm] rate was 79% (63/80), and obesity indicators [BMI, WC, waist-hip ratio (WHR), weight height ratio (WHTR), body roundness index (BRI), lipid accumulation index (LAP), visceral adiposity index (VAI)] were higher than those with endometrial benign lesions (all P<0.001). (2) Related factors affecting the efficacy of fertility preservation treatment and their predictive value: EC, higher BMI, WC, WHR, WHTR and BRI were risk factors for lower complete remission rate after nine months' treatment (all P<0.05). The predictive values of BRI and WHTR combined with pathological type were superior to other indicators [area under the curve (AUC)=0.716; AUC=0.714]. (3) Relation of obesity indicators and glucolipid indicators:BMI, WC, WHR, WHTR, BRI, LAP and VAI were positively correlated with homeostasis model assessment-insulin resistance index, glycosylated hemoglobin, and triacylglycerol (all P<0.05); while VAI was negatively correlated with high density lipoprotein cholesterol (P<0.001). Conclusions: For patients with EAH and EC treated with fertility preservation therapy, abnormal obesity indexes affect the treatment effect. BRI and WHTR combined pathology have good predictive value for effect of fertility preservation treatment. In clinical practice, appropriate indicators could be selected to evaluate body shape, glucolipid metabolism and predict efficacy.

IVF impact on the risk of recurrence of endometrial adenocarcinoma after fertility-sparing management.

RESEARCH QUESTION: Do IVF treatments after conservative management of endometrial atypical hyperplasia or grade 1 endometrial adenocarcinoma (AH/EC) increase the risk of disease recurrence? DESIGN: This is a prospective cohort study from a national registry from January 2008 to July 2019. Sixty patients had an AH/EC and received progestin treatment using chlormadinone acetate for at least 3 months. After remission, 31 patients underwent IVF and 29 did not. The primary outcome was the recurrence rate at 24 months according to the use of IVF. The secondary outcome was the identification of risk factors for recurrence. RESULTS: The probability of 2-year recurrence was 37.7% (SD 10.41%) in the IVF group and 55.7% (SD 14.02%) in the no IVF group (P = 0.13). Obesity, nulliparity, polycystic ovary syndrome, age and tumoural characteristics were not associated with recurrence. Pregnancy was a protective factor for recurrence, with 2-year recurrence probabilities of 20.5% and 62.0% in the pregnancy and no pregnancy groups, respectively (P = 0.002, 95% CI 0.06-0.61). In contrast, the number of cycles, maximum serum oestradiol concentration during ovarian stimulation, ovarian stimulation protocol, total dose of gonadotrophin administered and thickness of the endometrium showed no significant differences in terms of the risk of recurrence in the IVF subgroup. CONCLUSION: IVF treatment after fertility-sparing management of AH/EC does not increase the risk of recurrence. Therefore, it is an acceptable strategy to decrease the time to pregnancy. Overall, the recurrence rate is high enough to justify close monitoring once remission occurs.

Stem Cells and the Endometrium: From the Discovery of Adult Stem Cells to Pre-Clinical Models.

Adult stem cells (ASCs) were long suspected to exist in the endometrium. Indeed, several types of endometrial ASCs were identified in rodents and humans through diverse isolation and characterization techniques. Putative stromal and epithelial stem cell niches were identified in murine models using label-retention techniques. In humans, functional methods (clonogenicity, long-term culture, and multi-lineage differentiation assays) and stem cell markers (CD146, SUSD2/W5C5, LGR5, NTPDase2, SSEA-1, or N-cadherin) facilitated the identification of three main types of endogenous endometrial ASCs: stromal, epithelial progenitor, and endothelial stem cells. Further, exogenous populations of stem cells derived from bone marrow may act as key effectors of the endometrial ASC niche. These findings are promoting the development of stem cell therapies for endometrial pathologies, with an evolution towards paracrine approaches. At the same time, promising therapeutic alternatives based on bioengineering have been proposed.

Clinical Predictive Factors of Response to Treatment in Patients Undergoing Conservative Management of Atypical Endometrial Hyperplasia and Early Endometrial Cancer.

Purpose: Predictive markers of response to conservative treatment of atypical endometrial hyperplasia (AEH) or early endometrial cancer (EEC) are still lacking. We aimed to assess clinical predictive factors of response to conservative treatment of AEH and EEC. Methods: All patients with AEH or EEC conservatively treated from January 2007 to June 2018 were retrospectively assessed. The associations between 23 clinical factors and outcomes of response to treatment were assessed with standard univariate analyses and multivariate logistic regression (significant p-value <0.05). The primary outcome was the association of each clinical factor with treatment failure (i.e., no regression or relapse of the disease). Secondary outcomes were the associations of each clinical factor with: (1) no regression, (2) relapse, or (3) pregnancy after treatment. Results: Forty-three women, 37 (86%) with AEH and 6 (14%) with EEC were included. At univariate analyses, treatment failure was associated with longer menstrual cycle (p = 0.002), infrequent menstrual bleeding (p = 0.04), and a diagnosis of EEC instead of AEH (p = 0.008). Among the secondary outcomes, no regression was associated with infrequent menstrual bleeding (p = 0.04), and a diagnosis of EEC instead of AEH (p < 0.001), while relapse was associated with longer menstrual cycles (p = 0.007). At multivariate analyses, odds ratio for treatment failure was 4.54 (95% confidence interval [CI], 0.24-84.4) for a diagnosis of EEC instead of AEH (p = 0.3), and 2.10 (95% CI, 1.03-4.29) for longer menstrual cycles (p = 0.042), while infrequent menstrual bleeding perfectly predicted treatment failure. Conclusions: Longer menstrual cycles and infrequent menstrual bleeding appear as independent predictive factors for conservative treatment failure in AEH and EEC. Further and larger studies are necessary to confirm these findings.

Fertility-sparing management for endometrial cancer: review of the literature.

INTRODUCTION: Primary surgery is effective in low-risk endometrial cancer (EC). However, in young women, this approach compromises fertility. Therefore, fertility-sparing management in the case of atypical endometrial hyperplasia, or grade 1 EC limited to the endometrium can be considered. EVIDENCE ACQUISITION: We performed a literature review to identify studies involving women with EC or atypical hyperplasia who underwent fertility-sparing management. We conducted multiple bibliographic databases research from their inception to May 2020. EVIDENCE SYNTHESIS: Oral therapy with medroxyprogesterone acetate and megestrol acetate is recommended based on extensive experience, although without consensus on dosages and treatment length. The pooled complete response rate, recurrence rate, and pregnancy rate of EC were 76.3%, 30.7% and 52.1%, respectively. Endometrial hyperplasia was associated with better outcomes. LNG-IUSs appears an alternative treatment, particularly in patients who do not tolerate oral therapy. In a randomized controlled trial, megestrol acetate plus metformin guaranteed an earlier complete response rate than megestrol acetate alone for endometrial hyperplasia. Hysteroscopic resection followed by progestogens is associated with a higher complete response rate, live birth rate, and lower recurrence rate than oral progestogens alone. Pooled complete response, recurrence, and live birth rates were 98.1%, 4.8% and 52.6%. CONCLUSIONS: Fertility preservation appears feasible in young patients with grade 1 EC limited to the endometrium or atypical endometrial hyperplasia. Progestins are the mainstay of such management. The addition of Metformin and hysteroscopic resection seems to provide some improvements. However, fertility preservation is not the standard approach for staging and treatment, potentially worsening oncologic outcomes.

A survey of French gynecologists' knowledge and attitudes toward conservative treatment for fertility preservation in young patients with endometrial cancer.

OBJECTIVE: To describe knowledge and attitudes toward fertility preservation (FP) in patients with endometrial atypical hyperplasia or adenocarcinoma (EC/AH) among French gynecologists MATERIALS AND METHODS: A national survey among French gynaecologists: one questionnaire with one common part and two specific parts for gynecological surgeon (GS) or for specialists in reproductive medicine (SRM) was sent from April 2017 to April 2018. Knowledge and attitudes toward FP in EC/AH were evaluated with a "knowledge score" and an "attitudes score" using a four- or five-point Likert scale. RESULTS: One hundred forty physicians completed the survey (87 GS, 53 SRM). The knowledge score was low (59.3% medium/low), but it was significantly higher for GS compared to SRM. The better-known treatments were oral progestins and hysteroscopic resection. Among the participants treating EC/AH, 52.6% found it "difficult" to manage patients and 61.8% regretted the lack of official recommendations. Most physicians seemed to be uncomfortable/unsupportive with FP in EC/AH (57.2% "attitude score' below 11/20). There was a positive correlation between knowledge and attitude scores. GS "usually/always" give advice to patients about FP before EC/AH treatment. After maximum 3-6 months, 56.6% of SRM chose In Vitro Fecundation (IVF) to reduce time-to-pregnancy, with GnRH antagonist protocols (28%) or mild-stimulation (15.1%) to avoid hyperoestrogenism. CONCLUSIONS: Despite reassuring results in the literature, French gynecologists are uncomfortable with FP using EC/AH conservative management, which may be because of a lack of confidence in their knowledge. Specific guidelines are needed to help physicians manage these young patients and their fertility.

Fertility preservation in early-stage endometrial cancer and endometrial intraepithelial neoplasia: A single-center experience.

OBJECTIVE: The purpose of this study was to define the pregnancy and oncologic outcomes after fertility-sparing treatment of atypical hyperplasia (AH)/endometrial intraepithelial neoplasia (EIN) and early-stage endometrioid endometrial cancer (EEC). MATERIALS AND METHODS: The retrospective cohort study included patients who had applied to Baskent University's Ankara Hospital between January 2007 and October 2018 with either AH/EIN (n: 27; Group A) or EEC (n: 30; Group B), and who had the desire to preserve their fertility. The medical records of all patients included in the study were reviewed retrospectively from the hospital records. RESULTS: There were 2 (7.4%) and 5 (16.7%) recurrences, whereby one patient from Group A and two patients from Group B underwent staging surgery. In Group A, 8 patients attempted pregnancy after their treatment and 4 of them (50%) became pregnant, while 3 of them (37.5%) had a live birth. In Group B, there were 17 patients who wanted to become pregnant following treatment of the disease; 8 of them (47%) became pregnant after treatment, 5 of them (16.6%) had a live birth, 1 experienced intrauterine exitus (at 21st gestational week, 350 g), and 2 currently have ongoing pregnancies. CONCLUSION: Hysteroscopic resection of visible lesions and full endometrial curettage prior to hormonal therapy as a fertility-preserving approach for women of reproductive age with endometrial malignancies can achieve promising oncologic and obstetric responses.

[Clinical efficacy and pregnancy outcomes of fertility-preserving re-treatment after recurrence of the patient with atypical endometrial hyperplasia and early stage endometrial carcinoma].

Objective: To analyze the clinical efficacy and pregnancy outcomes of fertility- preserving re-treatment in patients with recurrent atypical endometrial hyperplasia (AEH) and early stage endometrial carcinoma (EEC) after achieved complete remission (CR) of primary fertility-preserving therapy. Methods: There were 104 cases of AEH and EEC collected from 9 hospitals in the multi-center research network platform of fertility-preserving therapy of endometrial carcinoma in China from January 2005 to May 2019. Thirth-one cases of them relapsed from four hospitals mentioned above,who achieved CR after primary fertility-preserving therapy,was analyzed retrospectively. Of the 31 cases, 27 cases chose fertility-preserving re-treatment. The demographic characteristics, re-treatment effect, clinical factors and pregnancy outcomes were observed. Results: (1) There were 16 AEH cases and 11 ECC cases among 27 recurrent patients who chose fertility-preserving therapy again. After re-treatment, CR was found in 13 out of 16 cases of AEH and 9 out of 11 cases of EEC. The overall CR rate was 81% (22/27). (2) After CR of recurrence, 5 cases (23%, 5/22) of re-recurrence were found after with a median time of 33 months (range 21-80 months). There were 4 cases underwent comprehensive surgical staging, and 1 patient chose the third round of fertility preservation therapy with fully informed consent, and CR was reached after 15 months. (3) There were 16 cases with pregnancy intention, with a total of 12 pregnancies, including 5 cases were natural pregnancy and 7 cases were assisted reproductive technology pregnancy. There were 5 live births. The follow-up time was up to May 2019, and the median follow-up time was 73 months (range 0-123 months). All 27 patients had disease free survival. Conclusions: Recurrent patients with AEH and EEC after achieving successful fertility-preserving therapy could choose fertility-preserving therapy again with comprehensive assessment and fully informed consent. After re-treatment, there is a certain tumor CR rate and pregnancy rate, while the close follow-up is required during treatment.

Conservative management of endometrial intraepithelial neoplasia in a patient with cirrhosis undergoing orthotopic liver transplant.

OBJECTIVE: The aim of the study was to review the management of endometrial hyperplasia in a woman undergoing liver transplantation for alcoholic cirrhosis. METHODS: This is a case presentation on a postmenopausal woman with a tissue diagnosis of endometrial intraepithelial neoplasia managed with a levonorgestrel intrauterine device, before and after liver transplantation. Full written informed consent was obtained from the patient to present her case. RESULTS: The patient experienced resolution of her endometrial intraepithelial neoplasia with conversion to atrophic endometrium after management with levonorgestrel intrauterine device. CONCLUSIONS: A large percentage of women with cirrhosis experience abnormal uterine bleeding, which may be due to the coagulopathy that accompanies liver disease, or endometrial hyperplasia or carcinoma. Although hysterectomy is the criterion standard of treatment for atypical endometrial hyperplasia in a postmenopausal woman, patients with cirrhosis severe enough to require transplant are usually poor surgical candidates. Multiple studies have shown success with conservative management of atypical hyperplasia. There is a paucity of literature on managing patients undergoing transplant with abnormal uterine bleeding and it is therefore important to highlight conservative management options for this patient population.

Lymph node micrometastases and outcome of endometrial cancer.

BACKGROUND: The relationship between nodal micrometastases and clinical outcome of endometrial cancer is unclear. PATIENTS AND METHODS: We performed a multicenter, retrospective registry-based study of 2392 patients with endometrial cancer with and without nodal micrometastases. The primary outcome measure was disease-free survival. RESULTS: After exclusions, the final study involved 428 patients: 302 (70.6%) with node-negative endometrial cancer, who did not receive adjuvant treatment, 95 (22.2%) with nodal micrometastases who received adjuvant treatment, and 31 (7.2%) with nodal micrometastases who did not receive adjuvant treatment. The median follow-up was 84.8 months. Without adjuvant therapy the disease-free survival in the cohort of patients with micrometastases was significantly reduced as compared with disease-free survival in the node-negative cohort (p = 0.0001). With adjuvant therapy the median disease-free survival of patients with nodal micrometastases was similar with those of node-negative patients (p = 0.648). The adjusted hazard ratio for disease events among patients with micrometastases and no adjuvant therapy, as compared with node-negative patients, was 2.23 (95% confidence interval [CI] 1.26-3.95). In the cohort with micrometastases the relative risk of events was significantly decreased by adjuvant therapy (HR 0.29, 95%CI 0.13-0.65) even after adjustment for age at diagnosis, myometrial invasion, histological grade and type, and performance status. CONCLUSIONS: Nodal micrometastases are associated with decreased disease-free survival of patients with endometrial cancer. Adjuvant therapy was associated with improved disease-free survival of patients with micrometastases.

Diabetes mellitus and responsiveness of endometrial hyperplasia and early endometrial cancer to conservative treatment.

Objective: The conservative treatment of endometrial hyperplasia without atypia (HWA), atypical endometrial hyperplasia (AH/EIN) and early endometrioid carcinoma (EEC) is based on progestins. We aimed to assess whether diabetes mellitus affects the responsiveness of HWA, AH/EIN and EEC to conservative treatment, through a systematic review and meta-analysis. Study design: Electronic databases were searched for studies assessing the outcome of conservative treatment in HWA, AH/EIN and EEC, stratified based on the diagnosis of diabetes mellitus. The association of diabetes mellitus with treatment failure was assessed by using odds ratio (OR). A p-value < .05 was considered significant. The risk of publication bias was assessed by using a funnel plot. A subgroups analyses was performed based on histologic diagnosis of benignity (HWA) or premalignancy/malignancy (AH/EIN or EEC). Results: Six studies with 876 patients (383 HWA, 365 AH/EIN and 128 EEC) were included. Overall, diabetes mellitus was not associated with outcome of treatment (OR = 1.20; p = .62). The association was not significant in both the HWA subgroup (OR = 0.95; p = .93) and in AH/EIN and EEC subgroup (OR = 1.43; p = .46). There was no significant risk of publication bias. Conclusions: Diabetes mellitus does not affect the outcome of conservative treatment in HWA, AH/EIN and EEC.

National patterns of care and fertility outcomes for reproductive-aged women with endometrial cancer or atypical hyperplasia.

BACKGROUND: Although it is uncommon, the incidence of endometrial cancer and atypical hyperplasia among reproductive-aged women is increasing. The fertility outcomes in this population are not well described. OBJECTIVE: We aim to describe the patterns of care and fertility outcomes of reproductive-aged women with endometrial cancer or atypical hyperplasia. MATERIALS AND METHODS: A cohort of women aged ≤45 years with endometrial cancer or atypical hyperplasia diagnosed in 2000 to 2014 were identified in Truven Marketscan, an insurance claims database of commercially insured patients in the United States. Treatment information, including use of progestin therapy, hysterectomy, and assisted fertility services, was identified and collected using a combination of Common Procedural Terminology codes, International Statistical Classification of Diseases and Related Health Problems codes, and National Drug Codes. Pregnancy events were identified from claims data using a similar technique. Patients were categorized as receiving progestin therapy alone, progestin therapy followed by hysterectomy, or standard surgical management with hysterectomy alone. Multivariable logistic regression was performed to assess factors associated with receiving fertility-sparing treatment. RESULTS: A total of 4007 reproductive-aged patients diagnosed with endometrial cancer or atypical hyperplasia were identified. The majority of these patients (n = 3189; 79.6%) received standard surgical management. Of the 818 patients treated initially with progestins, 397 (48.5%) subsequently underwent hysterectomy, whereas 421 (51.5%) did not. Patients treated with progestin therapy had a lower median age than those who received standard surgical management (median age, 36 vs 41 years; P < .001). The proportion of patients receiving progestin therapy increased significantly over the observation period, with 24.9% treated at least initially with progestin therapy in 2014 (P < .001). Multivariable analysis shows that younger age, a diagnosis of atypical hyperplasia diagnosis rather than endometrial cancer, and diagnosis later in the study period were all associated with a greater likelihood of receiving progestin therapy (P < .0001). Among the 421 patients who received progestin therapy alone, 92 patients (21.8%; 92/421) had 131 pregnancies, including 49 live births for a live birth rate of 11.6%. Among the 397 patients treated with progestin therapy followed by hysterectomy, 25 patients (6.3%; 25/397) had 34 pregnancies with 13 live births. The median age of patients who experienced a live birth following diagnosis during the study period was 36 years (interquartile range, 33-38). The use of some form of assisted fertility services was observed in 15.5% patients who were treated with progestin therapy. Among patients who experienced any pregnancy event following diagnosis, 54% of patients used some form of fertility treatment. For patients who experienced a live birth following diagnosis, 50% of patients received fertility treatment. Median time to live birth following diagnosis was 756 days (interquartile range, 525-1077). Patients treated with progestin therapy were more likely to experience a live birth if they had used assisted fertility services (odds ratio, 5.9; 95% confidence interval, 3.4-10.1; P < .0001). CONCLUSION: The number of patients who received fertility-sparing treatment for endometrial cancer or atypical hyperplasia increased over time. However, the proportion of women who experience a live birth following these diagnoses is relatively small.